Targeting NAT10 Induces Apoptosis Associated With Enhancing Endoplasmic Reticulum Stress in Acute Myeloid Leukemia Cells

Abstract

N-acetyltransferase 10 (NAT10) has oncogenic properties in many tumors through its role in different cellular biological processes. NAT10 is also a potential biomarker in acute myeloid leukemia (AML); however, the mechanisms underlying NAT10’s contribution to disease states and the effect of targeting NAT10 as a therapeutic target remain unclear. NAT10 was found to be highly expressed in patients with AML, and increased NAT10 expression was associated with poor outcomes. Additionally, targeting NAT10 via the shRNA knockdown and its pharmacotherapeutic inhibitor resulted in inhibition of cell proliferation, induction of cell cycle arrest in the G1 phase, and apoptosis in AML cells. Moreover, NAT10 induces cell cycle arrest by decreasing expression of CDK2, CDK4, CyclinD1, Cyclin E while simultaneously increasing the expression of p16 and p21. Targeting NAT10 induces ER stress through the increased expression of GRP78 and the cleavage of caspase 12, which are classical markers of ER stress. This triggered the Unfolded Protein Response (UPR) pathway by consequently increasing IRE1, CHOP, and PERK expression, all of which play crucial roles in the UPR pathway. Targeting NAT10 also activated the classical apoptotic pathway through the upregulation of the Bax/bak and the concurrent downregulation of Bcl-2. In summary, our data indicate that targeting NAT10 promotes ER stress, triggers the UPR pathway, and activates the Bax/Bcl-2 axis in AML cells. Our results thus indicate a novel mechanism underlying the induction of NAT10 inhibition-mediated apoptosis and reveal the potential for the therapeutic effect of a NAT10 specific inhibitor in AML.

Remodelin, a N‐acetyltransferase 10 (NAT10) inhibitor, alters mitochondrial lipid metabolism in cancer cells

“…Remodelin is a small molecule inhibitor of N‐acetyltransferase 10 (NAT10) reported to decrease protein expression of NAT10 and its downstream targets 1–4 . Studies have shown Remodelin to correct the defect of laminopathic cells, reduce viral copies in human immunodeficiency virus (HIV) and reverse cancer progression 5–7 .…”

“…Studies using Remodelin treated acute myeloid leukemia cell lines showed decreased antiapoptotic genes such as cyclin‐dependent kinase 2 ( CDK2), CDK4, cyclin D1 , and cyclin E, BCL2 , and an increase in proapoptotic genes such as p16 and p21 . Remodelin was also shown to affect the unfolded protein response pathway by altering IRE1, CHOP, and PERK protein expression 2 …”

“…Remodelin is a small molecule inhibitor of Nacetyltransferase 10 (NAT10) reported to decrease protein expression of NAT10 and its downstream targets. [1][2][3][4] Studies have shown Remodelin to correct the defect of laminopathic cells, reduce viral copies in human immunodeficiency virus (HIV) and reverse cancer progression. [5][6][7] In laminopathies such as Hutchinson-Gilford progeria syndrome, dysregulation of the nucleararchitecture proteins, lamin A and B causes deformed nuclei and altered chromatin organization.…”

“…Remodelin was also shown to affect the unfolded protein response pathway by altering IRE1, CHOP, and PERK protein expression. 2 Remodelin is reported to induce stress in colorectal cancer (CRC) by activating senescence-associated secretory phenotype (SASP) in the c-GAS-cGMP-STING pathway through the NAT10/cGAS/SASP axis. 3 In CoCl 2 induced hypoxia, the genes and protein levels of hypoxia-inducible factor 1α (HIF1α) and HIF2α were shown to decrease in HeLa and MCF-7 upon treatment with Remodelin suggesting its role in reversing the effect of hypoxia in endometrial cancer and breast cancer.…”

NAT10 as a Potential Prognostic Biomarker and Therapeutic Target for HNSCC

“…[16,31,32]. As the only ac4C modi cation producer, NAT10 is signi cantly associated with the prognosis of several malignant tumours and potently promotes the tumour progression [30,[33][34][35][36][37][38][39]. High expression of NAT10 in hepatocellular carcinoma [30,37,39] and colorectal cancer [38] is associated with a worse prognosis in patients.…”